Miles, John J., Borg, Natalie A., Brennan, Rebekah M., Tynan, Fleur E., Kjer-Nielsen, Lars, Silins, Sharon L., Bell, Melissa J., Burrows, Jacqueline, McCluskey, James, Rossjohn, Jamie, and Burrows, Scott R. (2006) TCR genes direct MHC restriction in the potent human T cell response to a class I-bound viral epitope. Journal of Immunology, 177 (10). pp. 6804-6814.

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Abstract

The underlying generic properties of αβ TCRs that control MHC restriction remain largely unresolved. To investigate MHC restriction, we have examined the CTL response to a viral epitope that binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (¹⁵⁶Leucine) or HLA-B*3508 (¹⁵⁶Arginine) showed a potent CTL response to the ⁴⁰⁷HPVGEADYFEY⁴¹⁷ epitope from EBV. Interestingly, the response was characterized by highly restricted TCR β-chain usage in both HLA-B*3501⁺ and HLA-B*3508⁺ individuals; however, this conserved TRBV9⁺ β-chain was associated with distinct TCR α-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR α-chain usage determined the HLA restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR α-chain usage is shown to play a critical role in controlling MHC restriction between closely related allomorphs.

Item ID:	45408
Item Type:	Article (Research - C1)
ISSN:	1550-6606
Funders:	Australian National Health and Medical Research Council (NHMRC), Roche Organ Transplantation Research Fund (ROTRF), Juvenile Diabetes Research Foundation (JDRF), Australian Research Council (ARC)
Date Deposited:	07 Sep 2016 04:06
FoR Codes:	11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes:	92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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